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Purpose: To examine the association between parity and long-term, all-cause mortality and mortality owing to specific causes in women., Methods: This prospective population-based study included 40,454 mothers who gave birth in Western Jerusalem, Israel, to 125,842 children and were followed for an average of 37 years after the birth of their first child. Cox proportional hazards models were used to evaluate long-term total and specific-cause mortality of women by their parity., Results: We found a U-shaped relationship between the number of offspring and risk of all-cause mortality in mothers. After adjustment for sociodemographic characteristics and maternal health and obstetric conditions, higher mortality rates were observed for mothers of 1 child (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.04-1.4), mothers of 5 to 9 children (HR, 1.21; 95% CI, 1.09-1.33), and mothers of 10 or more children (HR, 1.49; 95% CI, 1.12-1.99) compared with mothers of 2 to 4 children. Mortality risk from specific causes including coronary disease, circulatory disease, and cancer were increased for multiparous women., Conclusions: In this long-term follow-up study, there was an association between number of children and mortality risk for mothers. These findings suggest that maternal pregnancies and postnatal characteristics as reflected by number of children may have consequences for long-term maternal health., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Montelukast (Singulair) is a selective leukotriene receptor antagonist (LTRA) indicated for the maintenance treatment of asthma. Currently, there are limited prospective, comparative studies in the literature examining the safety of montelukast use in pregnancy., Objectives: The primary objective of this study was to determine whether exposure to montelukast during pregnancy increases the rate of major malformations above the 1–3% baseline risk or the rate of other adverse effects., Methods: Pregnant women taking montelukast were enrolled in the study from six teratogen information services around the world. These women were compared to two other groups of women: (1) disease-matched, who used inhalers for a similar indication and (2) women not diagnosed with asthma and not exposed to any known teratogens. The primary outcome was major malformations and secondary endpoints included spontaneous abortion, fetal distress, gestational age at birth and birth weight., Results: Out of 180 montelukast-exposed pregnancies, there were 160 live births including three sets of twins, 20 spontaneous abortions, 2 elective abortions and 1 major malformation reported. The mean birth weight was lower (3,214 ± 685 g) compared to controls [3,356 ± 657 (disease-matched) and 3,424 ± 551 (exposed to non-teratogens), P = 0.038] and the gestational age was shorter [37.8 ± 3.1 weeks (montelukast) and 37.6 ± 4.4 (disease-matched) versus 39.3 ± 2.4 weeks (exposed to non-teratogens), P = 0.045]. About 25% of the newborns had fetal distress, a higher rate than controls (P = 0.007). However, upon sub-analysis of women who continued the drug until delivery, only birth-weight difference (304 g) remained significant., Conclusions: Montelukast does not appear to increase the baseline rate of major malformations. The lower birth weight in both asthma groups is most likely associated with the severity of the maternal condition.

Purpose: To explore the association between birth weight in offspring, a marker of the intrauterine environment, and mortality in their mothers, taking into account maternal pre-pregnancy characteristics, including maternal body mass index (BMI), smoking, and socioeconomic status. Distinguishing the effects of offspring's birth weight and pre-pregnancy characteristics on maternal outcome may provide clues regarding mechanisms underlying the association between birth weight and maternal mortality., Methods: We studied long-term total mortality (average follow-up period, 29.1 years) in a population-based cohort of 13,185 mothers, aged 15 to 48 years at their offspring's birth, who delivered in West Jerusalem during 1974 through 1976., Results: Univariate and multivariate Cox-proportional hazard models used to estimate the hazard of overall mortality among mothers indicated a nonlinear relationship with birth weight of offspring when introduced into the models as a continuous variable, and a linear positive association with maternal pre-pregnancy BMI. Inclusion of maternal BMI and other pre-pregnancy characteristics in the model did not alter the association between offspring's birth weight and mothers' all-cause mortality. When birth weight was introduced as a categorical variable, higher mortality was observed among mothers who gave birth to babies with birth weight less than 2500 g (hazard ratio [HR] = 1.90; 95% confidence interval [95%CI], 1.23-2.94) as compared to mothers whose offspring had birth weight between 3000 and 3499 g. The HR for mothers who gave birth to babies with birth weight 4000 g or more was 1.30 (95%CI, 0.88-1.91)., Conclusions: Independent of pre-pregnancy maternal BMI and other characteristics, birth weight of offspring was associated with mortality in their mothers, suggesting that intrauterine metabolic events reflected by birth weight and not explained by maternal obesity, smoking, and socioeconomic status have remote consequences for maternal health. These findings underline the need to explore specific genetic and/or environmental mechanisms that account for these associations.

Background: Medication errors are a common cause of morbidity and mortality., Objectives: To evaluate the rate of acknowledgment of medication errors as reported by physicians working in the community and in hospitals., Methods: An anonymous questionnaire was sent to 9320 active physicians (about 48% community physicians, 17% hospital physicians and 35% working in both places), with questions on the rate and type of medication errors that they had encountered during their professional career. The questions specified errors in dosage, type of medicine (wrong indication), route of administration and drug interactions., Results: Only 627 physicians (6.7%) responded. Of these, nearly 79% admitted having made an error in prescribing medication; the majority admitted to more than one error. Physicians with fewer years of experience admitted having made a mistake more than did physicians with more experience (P = 0.019). Pediatricians and geriatricians made more dosage mistakes (P= 0.02), while family physicians and psychiatrists made more mistakes in drug interactions (P= 0.001)., Conclusions: It is possible that indifference, fear of identification, or lack of awareness may have contributed to the low response rate despite the fact that the questionnaire was anonymous. Educational programs should be implemented in medical schools to encourage physicians to report errors before the onset of adverse reactions.

Aims: Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine., Methods: This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first-trimester gestational exposure to paroxetine, fluoxetine or nonteratogens., Results: We followed up 410 paroxetine, 314 fluoxetine first-trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls [paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%)]. The main risk applied to cardiovascular anomalies [paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%)]. On logistic regression analysis only cigarette smoking of >or=10 cigarettes day(-1) and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively., Conclusion: This study suggests a possible association between cardiovascular anomalies and first-trimester exposure to fluoxetine.

Background: In recent years, mother to child transmission of human immunodeficiency virus in the west has decreased markedly due to the advent of antiretroviral drugs given during pregnancy, cessation of lactation, and careful monitoring of viral load in the perinatal period., Objective: To assess mother to child transmission of HIV among Ethiopian immigrants and non-Ethiopians in the Jerusalem area., Methods: We conducted a prospective analysis of all deliveries of HIV-positive women in the Jerusalem district over a 10 year period., Results: Between 1996 and 2006, 35 HIV+ women gave birth to 45 infants. Thirty-one (88%) of these women were of Ethiopian origin and gave birth to 39 infants. Of the 35 HIV+ women, 30 were aware of being HIV positive. They gave birth to 40 infants. Another 5 women (14%) were not aware of being HIV+ during delivery. They gave birth to five infants. Of the group of known HIV+ women, 26 (87%) were Ethiopian immigrants who delivered 34 infants and 4 were non-Ethiopians who delivered 6 infants. In the group of five women not aware of being HIV+, all were Ethiopians. Breast-feeding data were available for 32 of the 35 women. Only 2 women (6.2%) breast-fed their babies. Neither was aware of being HIV+. In the Ethiopian immigrant group (both known and unknown HIV status), 11 deliveries (28%) were vaginal, 18 (46%) were elective cesarean section and 10 (26%) were delivered by emergency cesarean section. Of the 26 known HIV+ Ethiopian women, 3 (12%) refused antiretroviral treatment despite repeated counseling. In the non-Ethiopian group, all deliveries were elective cesarean sections. Mother to child transmission of HIV occurred in 4 of the total 45 deliveries (8.8%). Of the 4 transmission cases, 2 occurred among 40 deliveries of known HIV+ women (5%), and 2 occurred among the 5 deliveries of women not aware of being HIV+ (40%, P=0.05). In the group of Ethiopian women only, HIV transmission occurred in 4 of 39 deliveries (10%), of which 2 occurred among 34 deliveries (5.8%) of women know to be HIV+ and 2 among 5 deliveries (40%) of women not aware of being HIV+ (P=0.08)., Conclusions: Pregnant Ethiopian immigrants whose HIV status was known during pregnancy were at relatively high risk of HIV transmission despite the availability of antiretroviral drugs and counseling. This is likely due to inadequate adherence to ART preventive regimens, not dissimilar to the poor adherence observed among other immigrant groups in western countries. The substantial proportion of women, all Ethiopians, unaware being HIV+ at delivery, together with the significantly higher HIV transmission in that group compared to women who knew their HIV status, call for a revision of the current Ministry of Health opt-in policy for prenatal HIV screening.

Background: Epstein-Barr virus (EBV) is one of the most common human viruses. To date, there is limited information regarding the influence of maternal EBV infection on pregnancy outcome., Objective: Our aim was to examine the fetal safety of EBV infection in pregnancy., Study Design: We prospectively evaluated the rate of major anomalies and pregnancy outcome of women with serologic evidence of primary, recurrent or undefined infection (27, 56, and 43 women, respectively) compared to 1434 women who called the Israeli TIS for non-teratogenic exposure., Results: Women's characteristics and pregnancy outcome were comparable between the EBV exposed and control groups. Similarly, the gestational age at delivery and birth weight were not significantly different. The rate of major congenital anomalies did not significantly differ between the EBV exposed compared to the control group., Conclusion: This study suggests that EBV infection during pregnancy does not represent a major teratogenic risk to the fetus.

A patient with multiple myeloma (MM) was being maintained on human recombinant interferon-alpha (INF-alpha) after VAD and autologous bone marrow transplantation (pretreated with melphalan). An episode of immune thrombocytopenia and (Coombs positive) autoimmune hemolytic anemia (AIHA) was noted while on maintenance INF-alpha, which remitted when it was withdrawn. Following this event, he achieved a state of stable disease that persists (more than 3 years) with no specific myeloma treatment. This sequence of events suggests a relationship between an immunological reaction induced by INF-alpha and the prolonged phase of stable disease., ((c) 2007 Wiley-Liss, Inc.)

Background: Chronic graft versus host disease (GvHD) is a major complication after allogeneic stem cell transplantation (SCT), which is usually progression from acute GvHD. Chronic GvHD is the main cause of severe morbidity and mortality in long-term survivors after SCT. The cysteinyl leukotrienes (cysLTs) and eosinophils play an important role in the pathogenesis of GvHD, which is the rationale for the combined use of montelukast (Mk) in the treatment of this illness., Methods: Mk was administrated to 19 eligible patients with refractory chronic GvHD, in addition to their standard immunosuppressive regimens. Mk was given orally (10 mg once daily) for a mean period of 10 months (range, 2-21 months). Organ-specific response was determined by the new scoring criteria established by the National Institutes of Health consensus project., Results: Based on organ involvements endpoints, overall response to the combined therapy with Mk was observed in 15 of 19 (79%) patients. Significant improvement of skin liver and gastrointestinal was observed in 53%, 62%, and 46%, respectively. Generally, Mk was notably beneficial in milder stages of GvHD, which lead to earlier withdrawal of other immunosuppressive agents. Side effects of Mk administration were not documented, nor were cases of relapse of the basic disease., Conclusions: Our preliminary prospective investigation supports the potential efficacy of Mk as a safe and toxicity-sparing supplement to standard therapy for patients with chronic GvHD. Future clinical studies are necessary to establish the optimal dose of Mk and its role in the symptomatic and prophylactic treatment of acute and chronic GvHD.

Introduction: Diabetes mellitus (DM) during pregnancy is associated with an increased risk for poor reproduction and a high rate of congenital malformations. The gerbil Psammomys obesus is a unique model for nutritionally induced Type 2 DM (T2DM) that enabled us to study the outcome of uncontrolled T2DM during pregnancy., Methods: Female Psammomys on low-energy (LE) or high energy (HE) diet were studied. The blood glucose levels and weights of pregnant animals were determined. The offspring from the different groups were followed-up to weaning., Results: Most of the HE-diet animals were diabetic (77%). There were no differences in the pregnancy rates in animals on both diets (32.7% in HE vs. 38.3% in LE). Pregnancy of the HE-diet group was longer than the LE-diet group (26.7 vs. 26.1 days), and litter average was reduced (2.7 vs. 3.0). At birth, the offspring of the HE-diet dams weighed less (5.2 vs. 7.2 g) and had smaller crown rump length (4.0 vs. 4.6 cm) These offspring also presented a 1-3 days delay in neuro-developmental parameters (first turn over, hair appearance, eye-opening and response to noise). However, from the fourth week of life they became diabetic, and from the third week they weighed more than the LE offspring., Conclusion: HE-diet caused diabetes, maternal complications and altered reproduction in Psammomys animals. The offspring of diabetic Psammomys presented birth weight and length changes as well as developmental delay., (Copyright 2006 S. Karger AG, Basel.)

Embryonic and fetal growth depend on genetic and environmental factors, and the process is the result of the interaction between these factors. About 7-9% of live-born infants have a birth weight below normal (below the 10th percentile). The rate and extent of intrauterine growth restriction (IUGR) varies by ethnicity and socio-economic status. Some of the suspected causes of IUGR are as follows. (1) Maternal factors such as inadequate or severe malnutrition, chronic maternal diseases, birth order, multiple births, and parental genetic factors. (2) Placental pathology, mainly placental vascular damage that may lead to placental insufficiency. This is often found in maternal diseases such as pre-eclampsia, and Thrombophilia. (3) Intrauterine infections and specific fetal syndromes, including chromosomal aberrations. (4) Non-classified causes such as adolescent's pregnancy, maternal smoking and alcohol drinking, living at high altitudes. Several existing animal models for IUGR, including uterine artery ligation or gene knock out models, although insightful of potential mechanism(s) underlying intrauterine growth restriction, are limited in that they do not reflect human causality. As the ultimate goal is prevention, we seem still to be distant from achieving this goal.

Repeated doses of acetaminophen given for therapeutic reasons have been reported to cause hepatotoxicity in adults and children. We studied the effect of repeated acetaminophen (APAP) overdoses administered for therapeutic purposes in a prospective cohort of children. Forty-four children, aged 2 mo to 10 y were referred with a fever of >38.5 C for more than 48 h, and received >60 mg APAP/kg/d. In each patient AST, ALT and APAP blood levels were measured. The mean total daily dose of APAP was 92+/-26 (63-171) mg/kg. There was a weak, but significant, negative correlation between age and daily dose of APAP where younger children received higher doses of APAP. In 4 children (9.1%) an elevation of AST and ALT was found. Three of the 4 patients with elevated liver enzymes had received >90 mg APAP/kg/day; APAP blood levels ranged from 0 to 23 mg/mL. No correlation was found between the time since last APAP dose and the serum drug level. Ill children receiving repeated supratherapeutic doses of acetaminophen may show abnormalities in liver function. However, severe liver injury was rare.